• Nathan Riley, MD

Obgyno Wino Podcast Episode 86 - Endometrial Cancer

“The first step is to direct the soul's attention toward certain processes in the world around us. These processes are life, as it buds, grows, and flourishes; and, on the other hand, all phenomena connected with withering, fading, and dying away. Wherever we turn our eyes, these two processes are present together. By their nature, they always evoke feelings and thoughts in us. Normally, however, we do not give ourselves sufficient to these feelings and thoughts. We rush from one sense impression to the next. Now, however, we must consciously and intensively focus our full attention on them. Whenever we perceive a quite definite form of blossoming and flourishing, we must banish all else from our souls and, for a short time, dwell on this one impression alone." - Rudolf Steiner

2016 Chianti Classico Riserva by Cavaliere d'Oro

PB #149 - Published April 2015 (Reaffirmed 2017)

Five Pearls

1. When EIN is absent, risk of progression to carcinoma is 1-8%, risk is much higher when EIN present.

2. For any patient with abnormal uterine bleeding in the context of risk factors for endometrial cancer, endometrial biopsy (EMB) is reasonable.

3. Surgical staging for endometrial cancer consists of removal of the uterus, cervix, adnexa (fallopian tubes, ovaries, and adjacent tissues), lymphadenectomy (pelvic and/or para-aortic), and pelvic washings

4. If EEC is ≤ 4 mm on US for a woman with postmenopausal bleeding, EMB is not required, as risk of malignancy is teeny tiny. If >4 mm, biopsy by EMB, sonohysterography, or hysteroscopy is warranted.

5. Optimal surgical cytoreduction (removal of all visible cancer) is most crucial aspect. It has the greatest impact on progression-free and overall survival rates.

6. For survivors of endometrial cancer, surveillance includes q3 months for 2 years followed by q6 months for 3 years, then annually thereafter indefinitely (until she decides to stop coming!)

Endometrial cancer is a common malignancy in the gyn world

- Caucasian and black women have ~2.5% lifetime risk

- >70% of cases are stage I at time of diagnosis; 90% 5-year survival rate

- mean age in the U.S. is 63; 5% diagnosed before age 40, 15% before age 50, and

- black women are more likely, however, to have Type II cancer

- Type I: endometrioid, "low grade", better prognosis, usually stage I at time of diagnosis,

- Type II: nonendometrioid, clear cell and serous tumor histologies, "high grade", worse prognosis, usually stage III or IV at time of diagnosis; 10% of cases but accounts for 40% of deaths; associated with smoking

- carcinosarcoma is in a class of its own: aka "malignant mixed mullerian tumor", terrible prognosis

Precancerous lesions

- two schematics of nomenclature

- WHO schematic: atypical endometrial hyperplasia; classic

- IECG schematic: endometrial intraepithelial neoplasia (EIN)

- IECG schematic increasingly preferred because it clearly distinguishes between distinct clinicopathologies that are managed differently

- when endometrial hyperplasia (WHO schematic) is absent, risk of progression to carcinoma is ~5% over 12 years

- when EIN (IECG schematic) is absent, risk of progression to carcinoma is 1-8%, depending on the degree of architectural complexity

- when EIN is present, is much more likely to progress to cancer, and 30-50% of the time there is concurrent carcinoma

- in a study of 306 with EIN who underwent hysterectomy, final path showed myometrial invasion in 43% (most were grade 1 and minimally invasive; however, 10% showed deep invasion)

Risk factors are listed in Table 1

Unopposed estrogen

- chronic anovulation (e.g. PCOS), estrogen-producing tumor, and excessive peripheral conversion of androgen to estradiol (e.g. obesity)

- hormone replacement therapy, particularly if BMI >27

- including progestin therapy mitigates risk to some degree (oral medroxyprogesterone or levonorgestrel-releasing IUDs)

- HTN and type II diabetes are associated, but difficult to separate its effect from obesity

- one study did find an independent association between diabetes and endometrial cancer, which could make sense given the leading theory of cancer as a metabolic disease

Selective estrogen receptor modulators

- examples include tamoxifen

- use is associated with decreased risk of primary breast cancer and recurrence, but increased risk of endometrial cancer in women ≥50 years

- Raloxifene protects against breast cancer without an increased risk of endometrial cancer

- data is lacking for ospemifene, but available evidence suggests no increased risk

Lynch syndrome and Cowden disease

Lynch: increased risk for endometrial, colorectal, and ovarian cancers

- due to germline mutations in mismatch repair genes (MLH1, MSH2, PMS2, and MSH6)

- up to 15-60% risk of endometrial cancer by age 70, depending on specific mutation

Cowden: increased risk for endometrial, thyroid, and breast cancers

- not much else to say about this from practice bulletin

Factors that decrease lifetime risk

- use of COCs

- use of depot medroxyprogsterone acetate (DMPA)

- use of levonorgestrel-releasing IUDs

- hysterectomy

Diagnosis - premenopausal women

- most common presenting sign if abnormal uterine bleeding or postmenopausal bleeding

- can present with bulk symptoms or symptoms similar to advanced ovarian cancers: pelvic pain/pressure, abdominal distension, bloating, early satiety, and changes in bowel/bladder function

- if any of the risk factors listed in Table 1 are present, reasonable to offer endometrial sampling but no cost-effective universal screening methods have been identified for low-risk women

- endometrial echo complex (EEC or "stripe") ultrasound measurement alone in premenopausal women is not useful

- if cancer if found on sampling by office EMB, D&C, sonohysterography, or hysteroscopy, surgical planning is the next step

Diagnosis - postmenopausal women

- any postmenopausal bleeding warrants evaluation for malignancy (EMB or EEC measurement by US)

- if EEC <3 mm, US is 98% sensitive for detecting malignancy; as such, ACOG suggests that if EEC is ≤ 4 mm, EMB is not required (unless bleeding is persistent!)

- if >4 mm, endometrial sampling is warranted

Best method for sampling endometrium

- dilation and curettage (D&C) has been the classical approach to endometrial sampling; however, office sampling with disposable devices is now considered reliable and just as accurate

- if you do D&C, best to simultaneously do hysteroscopy in order to do more directed sampling of discrete lesions while also sampling background endometrium

- if EMB is benign but bleeding persists, hysteroscopy w/ D&C is warranted

Who needs surgical staging (GOG 33)?

- Per GOG 33, comprehensive staging is recommended for any patient in which extrauterine spread is suspected (e.g. pre-operative histology demonstrating high-grade carcinoma including grade 2 or 3 endometrioid, papillary serous, clear cell, and carcinosarcoma)

- pre-operative evaluation for metastatic disease by CT, MRI, or PET/CT can be helpful for surgical planning, esp if your patient has comorbidities that would predispose them to greater risks from comprehensive surgical staging

- imaging can also be helpful if you suspect metastatic disease based on symptoms (e.g. neurological deficits, dyspnea)

- comprehensive staging helps in planning adjuvant therapies; however, risk of lymphadenectomy includes chronic lymphedema (~50% incidence), associated cellulitis, or injury to adjacent nerves/vessels --> everything comes with risk!

What is included in surgical staging?

- includes removal of the uterus, cervix, adnexa (fallopian tubes, ovaries, and adjacent tissues), lymphadenectomy (pelvic and/or para-aortic), and pelvic washings

- sampling lymph nodes from multiple sites is associated with better survival

- pelvic lymphadenectomy includes nodes from:

  • distal half of the common iliac arteries

  • anterior and medial aspect of external iliac artery and vein down to the point at which the deep circumflex iliac vein crosses the external iliac artery

  • obturator fat pad anterior to the obturator nerve

- para-aortic lymphadenectomy includes nodes from

  • distal inferior vena cava from the level of the inferior mesenteric artery to the midright common iliac artery

  • between the aorta and left ureter from the inferior mesenteric artery to the midleft common iliac artery

- if you need to pick one, just go for pelvic lymph nodes (risk of isolated para-aortic lymph node involvement is 1-3.5%)

What if she wants to keep her ovaries?

- the reason for BSO is that the ovaries can be a site for occult extrauterine spread (~20% incidence)

- estrogen production may also predispose her to earlier recurrence

- data is limited, some say removal of ovaries is a bad idea others suggest that it's reasonable (ACOG concludes that "BSO should be strongly considered")

Who should do the surgery?

- a generalist gynecologic surgeon can handle low-grade, minimally invasive disease

- HOWEVER, after the uterus, cervix, and adnexa are removed by the generalist, final histopathologic evaluation may reveal a different scenario from what you gathered from the initial endometrial sampling

- if this occurs, a second surgery by a gyn-oncologist for comprehensive staging will be required (no good...)

- every woman deserves a high volume surgeon. Put down the scalpel and refer to a gyn-oncologist if:

  • you won't be able to call them intraoperatively if you find something suspicious

  • pre-op histology demonstrates high-grade carcinoma

  • evidence of extrauterine disease on pre-op imaging

  • disease recurrence is diagnosed or suspected

  • nonoperative therapy is desired

If you conclude early stage disease (GOG 99)...

- the disease is confined to the uterus: probably no additional treatment required

- however: GOG 99 described a "high-intermediate risk" category for stage 1 or stage 2 disease, which included grade 2 or 3, myometrial invasion to outer one-third, and lymphovascular space invasion

- in women ≥70 with 1-of-3, women ≥50 with 2-of-3, and any women with 3-of-3, post-surgery radiation treatment may improve progression-free survival and decrease likelihood of local recurrence

- even without pelvic radiation, recurrence of early stage disease will likely respond quite well to salvage therapy

Minimally-invasive surgery is usually the best option even for comprehensive surgical staging (GOG LAP2)

- avoid the big giant abdominal incision whenever possible!

- in GOG LAP2, over 2000 women were randomized to laparoscopy or laparotomy in 2:1 fashion; 25% conversion from lsc --> lap

- laparoscopy (traditional or robot-assisted) takes longer but no difference in intraoperative complications when compared to laparotomy

- shorter hospital stay and higher quality of life during recovery after laparoscopy

- no difference in survival between the two approaches

- vaginal approach may be appropriate in patients with significant comorbidities if early stage disease suspected

Note: for a comprehensive review of the most cited Gynecologic Oncology Group (GOG) studies go here and here.

Radiation therapy for early stage disease

- as mentioned before, early stage disease with "high intermediate" risk factors may benefit from pelvic radiation or vaginal brachytherapy (PORTEC trial and this GOG study) to decrease risk of local recurrence

- vaginal brachytherapy is generally better tolerated (fewer GI side effects) than whole pelvic radiation

- vaginal brachytherapy (even in absence of staging) may be sufficient if certain risk factors:

  • > 60 years with stage IB grade 1 or grade 2 disease

  • > 60 years stage IA grade 3 disease w/ myometrial invasion

  • any age with endocervical glandular involvement and disease otherwise confined to the uterus excluding those with stage IB grade 3 disease

- for early stage disease, risks of adjuvant chemotherapy outweigh benefits

Note: everybody in the GYN/ONC world disagrees with optimal adjuvant therapy for early stage endometrial cancer

More advance disease or recurrent disease

- a multi-modal approach is key: surgery, chemo, and radiation

- optimal surgical cytoreduction (removal of all visible cancer) is most crucial aspect; has the greatest impact on progression-free and overall survival rates

- `median survival 15 months if <1cm residual disease remaining after primary surgery

- median survival 40 months if all visible tumor is removed during primary surgery

- same goes for secondary cytoreductive surgery in the event of recurrent disease

- if patient has undergone radiation, pelvic exenteration is the only curative option

Note: pelvic exenteration is horrible. All reproductive organs are removed (if they haven't been already). The peritoneum overlying the pelvis is removed. Often the rectosigmoid colon and bladder are removed, necessitating urinary and fecal diversion (nephrostomies and colostomy). Carries a high morbidity (60-80%) and mortality (10-15%)

Adjuvant therapies for advanced disease

- even with optimal cytoreduction to microscopic residual, adjuvant chemo is recommended to decrease risk of recurrence (adding radiation may improves outcomes even further)

- best results (5-year survival rate of 80%) seem to come with dual-agent chemo (cisplatin plus paclitaxel) with radiation treatments "sandwiched" between the chemo sessions (more here)

- if disease is found in the para-aortic lymph nodes, better to go with adjuvant chemo followed by "extended-field" (whole pelvic and para-aortic) radiation (5-year survival rate of 75%)

What if my patient doesn't want chemo or radiation?

- hormone replacement therapy (HRT) or tamoxifen may be helpful even in advanced disease irrelevant of hormone receptor status, but data is limited

- regimens include daily tamoxifen with alternating weekly medroxyprogesterone acetate or 3-week alternating cycles of megestrol acetate and tamoxifen

Fertility-sparing options

- 30% of patients diagnosed with endometrial cancer are <54 yrs; 9% <44 yrs

- limited data to guide therapy, unfortunately

- if diagnosis was made by EMB, best to get more tissue to fully clarify the histologic type and grade of disease (10% of uterine cancer cases are upgraded after hysterectomy when initial diagnosis is made by D&C compared to 25% made by EMB)

- CT/MRI may also be helpful in determining depth of invasion or presence of extrauterine disease

- treatment consists of progestin therapy (either medroxyprogesterone acetate or megestrol acetate) w/ repeat endometrial sampling q3 months

- get as soon as possible when the neoplasia resolves!

- if conservative measures fail (or after completion of childbearing), definitive surgical management is recommended

What if cancer is found incidentally on pathologic evaluation of the uterus after hysterectomy for other indications?

- hmmm...tastes like dill

- ask for close review of the histopathology of the neoplasia

- risks of repeat major surgery must be weighed against the benefits of comprehensive staging

- also: is she a good surgical candidate?

- if low grade endometrioid, risks may outweigh benefits (low risk for extrauterine spread or recurrence)

- if high grade clear cell or serous or myometrial invasion is deep, benefits may outweigh risks

What's the ideal surveillance protocol after primary therapies are completed?

- q3 months for 2 years followed by q6 months for 3 years, then annually thereafter indefinitely (until she decides to stop coming!)

- ROS, vaginal cuff check inspection, bimanual exam, rectovaginal exam

- CXR, CT, and PET/CT not recommended unless there's already high suspicion for recurrence

I have a history of endometrial cancer. Can I take HRT for menopausal symptoms?

- big issue for pre-menopausal women or women who are already transitioning (25% of total patients diagnosed), but even postmenopausal women may experience symptoms with the abrupt removal of ovaries

- the GOG tried to study this, but it didn't go the distance due to concerns about being able to recruit sufficient numbers given the rarity of recurrence (but prelim results looked promising)

- ACOG concludes that for patients with stage 1 or stage 2 disease estrogen therapy for menopausal symptoms is reasonable (risks versus benefits counseling)

Recall: progestins aren't needed in the regimen. Estrogen alone is sufficient. Progestins are only important when the uterus is still in place as a means of avoiding the risk that unopposed estrogen poses with regards to the development of endometrial cancer. Full circle!

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